Use of polyols in combating yeast infection and polyol preparations for said use

ABSTRACT

The invention relates to the use of polyols such as xylitol for the preparation of a composition to be administered in the treatment or prophylaxis of mucosal yeast infection in mammals, as well as to preparations for use in the systemic or topical therapeutic or prophylactic treatment of mucosal yeast infections. The invention relates specifically but not solely to the combating of infections caused by Candida s.p. in mucosa in connection with exocrine glands of the mammalian body.

The present invention relates to the use of polyols such as xylitol forthe preparation of a composition to be administered in the treatment orprophylaxis of mucosal yeast infection in mammals, as well as topreparations for use in the systemic or topical therapeutic orprophylactic treatment of mucosal yeast infections. The inventionrelates specifically but not solely to the combating of infectionscaused by Candida s.p. in mucosa in connection with exocrine glands ofthe mammalian body.

Despite the availability of effective antifungal drugs, optimalprophylactic and therapeutic approaches for mucositis are stillcontroversial. Factors that might have a stimulatory effect on fungalgrowth or decrease the effectiveness of antifungal therapy of mucositishave received little attention.

Oral candidiasis is the most common opportunistic infection in AIDS,affecting up to 90% of the patients. It importantly interferes withnutrition. Studies suggest that the presence of oral candidiasisincreases progression to AIDS, and that oral candidiasis is anindependent risk factor for the development of Pneumocystis cariniipneumonia. Oral candidiasis is also one of the most common reasons forpremature cessation of chemotherapy in cancer patients.

Optimal prophylaxis and therapy of oral candidiasis are stillcontroversial issues. Oral nystatin and amphotericin B are usuallyeffective, but compliance is problematic due to the unpalatable tasteand gastric intolerance of these compounds. Drugs based on azoles arealso effective, but resistance is an increasingly recognized problem.Recurrences are common. These issues warrant the search for novelstrategies to prevent or treat candidiasis.

It is known that sucrose favours the growth of Candida in vitro andsucrose rinses have been thought to induce the development of oralcandidiasis in some patients with dentures. Sucrose also increasesgastrointestinal growth and mucosal invasion of Candida albicans inmurine models.

Sucrose is the most commonly used sweetener for food and pharmaceuticalcontexts. Although a wide variety of alternate sweeteners are available,sucrose is generally considered to be the optimum sweetener with regardto taste profile and technological properties However, sucrose has beenimplicated as a contributory factor in many diseases includinghypertension. coronary heart disease, arterial sclerosis and dentalcaries.

Perhaps the most significant, well-documented effect of sucrose is itscontribution to tooth decay. The mouth contains a number of bacterialstrains which ferment common dietary carbohydrates such as sucrose. Thisfermentation generates acid as an end product which lowers the pH in themouth; the lowered pH leads to a demineralization of tooth enamel andfinally to the formation of dental lesions of caries.

One approach to fighting dental caries is to reduce or eliminate theamount of fermentable carbohydrates such as sucrose in pharmaceutical orfood contexts. The replacement of fermentable carbohydrates by sugarsubstitutes which cannot be fermented, or are less easily fermented byS. mutans and other bacteria has been shown to decrease the developmentof dental caries.

Xylitol is a naturally occurring five carbon sugar alcohol which has thesame sweetness as sugar and a caloric content which is less than that ofsugar. Xylitol is found in small amounts in many fruits and vegetablesand is produced in the human body during normal metabolism. Xylitol isattractive as a sugar substitute in food contexts because of its knownmetabolic, dental and technical characteristics.

Xylitol has been used as a sugar substitute in certain contexts, such aschewing gum [U.S. Pat. No. 4,514,422 (Yang) and 3,422,184 (Patel)] withpractical and commercial success. Xylitol has also been used in tablets[WO 92/10168 (Xyrofin Oy)], in sweets and chocolate, etc.

From a metabolic perspective, xylitol is metabolized largely independentof insulin, so it can be safely consumed by non-insulin dependentdiabetics. A significant advantage of xylitol is that it is notfermented by S. mutans and other bacteria found in the mouth and,therefore, does not produce acids which, as described above, contributeto the formation of dental caries. Xylitol is well established as anon-cariogenic substance, i.e. xylitol does not contribute to cariesformation. Significant data also exists which supports the view thatxylitol is not only non-cariogenic, but actively suppresses theformation of new caries and may even reverse existing lesions byinducing remineralization, i.e. it is a cariostatic material.

A summary of clinical data regarding the effects of xylitol and itspossible mechanisms is set forth in Bar, Albert, Caries Prevention WithXylitol: A Review of a Scientific Evidence, 55 Wld. Rev. Nutr. Diet.183-209 (1983). The mechanism or mechanisms by which xylitol effects anycariostatic properties is not yet known, but some possible mechanismswhich have been suggested include a reduction of oral levels of S.mutans, a reduction in the development of plaque, the stimulation of theflow of protective saliva, the favorable alteration of the compositionof saliva, the retardation of demineralization and a enhancement ofremineralization of tooth enamel.

Other polyols, such as sorbitol, mannitol and lactitol have also beensubstituted for sucrose in a variety of contexts. All of these polyolshave certain advantages, such as non-cario-genicity, over sucrose.However, none of the other polyols have been demonstrated to have acariostatic effect. Xylitol is also known to have a better patientcompliance than other polyols.

In a study examining the oral microflora in relation to caries, it wasfound (M. Larmas, et al., Acta Odontologica Scandinavia, Vol. 33, Suppl.70, 1975, p. 45-55) that substituting xylitol for sucrose in the diet ofa human test group during 8 months significantly reduced the number ofpersons with salivary Candida growth, while there was a slight increasein the test groups receiving sucrose and fructose. At the base linepractically every second person had Candida in the saliva.

Xylitol has been documented [S. L. Vargas et al., Infect. Immun. 1993;61(2):619-26] as a potential candidate for replacing glucose in animmunocompromised murine model of gastrointestinal candidiasis, as itdid not increase Candida growth nor invasion compared to controls whengiven instead of glucose. Mice receiving xylitol had five times lessinvasion of gastrointestinal mucosa by Candida, than did mice receivingglucose. Xylitol scores of invasion were not significantly differentfrom those of the control mice receiving no sugar.

A two month regular use of xylitol chewing gum has been shown to reducethe occurrence of acute otitis media in children [M. Uhari, et al., BMJ,Vol. 313 (1996); 1180-1184]. The effect was attributed to the efficacyof xylitol in reducing the growth of S. pneumoniae and thus preventingthe attacks of acute otitis media caused by pneumococci.

The occurrence of mucositis and especially oral candidiasis in AIDSpatients is an increasing problem in the world. Antifungal therapieshave not proven successful in all cases and fungal resistance to theavailable drugs is a frequent problem. Oral candidiasis is very painfuland provides the patients with a poor quality of life. There is felt tobe a real need for improving the available therapies for mucositis.

Despite the fact that the beneficial effect of replacing sucrose withxylitol in combating dental caries has been known for a long time andalthough xylitol was found not to increase gastrointestinal candidiasisas much as sucrose, no suggestion has been made for utilizing xylitol orother polyols for combating mucositis caused by yeasts on mucosa inclose connection with exocrine glands of the body.

The present inventors have now surprisingly found that a polyol such asxylitol has a marked beneficial effect in preventing yeast growth onmucosa at various orifices of the body and that said polyol consequentlyis useful in the treatment and prevention of mucositis in such areas inmammals. A polyol according to the present invention indicates a polyolsuch as xylitol, lactitol, mannitol, sorbitol or mixtures thereof.Xylitol is the preferred polyol. Thus, when the present specificationmentions xylitol as the polyol, this is indication of the preferredembodiment, but it should be observed that said mention is intended tocover also the other polyols which function in the same way. However,the inventors have found that the effect of xylitol is significantlybetter than that of other known polyols such as sorbitol and lactitol.Its effect seems not to be contributable only to a reduction in theamount of fermentable carbohydrates. Xylitol has been found to improvethe conventional antifungal therapies when administered in combinationwith such drugs.

The present invention accordingly provides a new use of a polyol such asxylitol in the preparation of a composition to be administered in thetreatment or prophylaxis of mucosal yeast infection in mammals.According to the invention at least one pharmacologically acceptablecarrier is mixed with an amount of xylitol sufficient to reduce orinhibit mucosal infection caused by yeasts such as Candida s.p. in saidmammal.

The invention offers a method for improving the therapeutic and/orprophylactic treatment of mammals suffering from or being subject to anincreased risk of mucosal yeast infection, said method comprisingadministering a polyol such as xylitol to said mammal in an amount whichis effective in reducing or inhibiting mucosal infections caused byyeasts such as Candida s.p in said mammal. The therapeutic treatment mayfavorably include a simultaneous administration of antifungal drugs.Generally the antifungal drug is administered at a dose level below thelevel given when not in combination with xylitol.

Thus, a synergistic effect can be observed when xylitol is administeredin combination with conventional antifungal drugs.

According to the invention xylitol may be incorporated into acomposition or a pharmaceutical preparation for use in the systemic ortopical therapeutic or prophylactic treatment of mucosal yeastinfections in mammals. Such a composition or preparation contains atleast one pharmacologically acceptable carrier and an amount of xylitolsufficient to reduce or inhibit mucosal infection caused by yeasts, suchas Candida s.p. in said mammal, or sufficient to enhance the effect ofother antifungal drugs used in the treatment of said infection.

In a preferred embodiment of the invention the mucosal infection to betreated is caused by a Candida s.p. yeast such as Candida albicans,especially in mucosa in connection with exocrine glands of the body ofthe mammal. Another genus of opportunistic yeasts which may causeinfections are Torulopsis s.p., especially Torulopsis glabrata. BothCandida albicans and Torulopsis glabrata are part of the normal flora ofthe mouth and vagina or urinary tracts of mammals. However, underfavourable conditions they cause infections of the mucosa.

It is to be noted that although the mammal in question may be selectedfrom the group comprising human beings, mammalian pet animals such ascats and dogs, mammalian farm animals such as horses, cattle, pigs, andthe like, the greatest problems are generally observed with human beingswho suffer from reduced immune defense such as AIDS patients.

AIDS patients are especially prone to suffer from oral yeast infections,especially oral candidiasis or thrush, which causes great pain at alltimes and especially in connection with food intake.

Mucosal infections in connection with exocrine glands may, however,occur also as mastitis, vaginal infection, as infections of the urinarytracts or even in the eyes. Animals may also suffer from yeastinfections on mucosa and an example is udder infection or mastitis inmilking cows.

In the practice of the present invention, the polyol such as xylitol isincorporated into a pharmaceutical composition to be administered viasystemic or topical administration. Xylitol may be used alone or incombination with various antifungal drugs effective in the combating ofthe mucositis. In some cases the effective drug has a unpleasant taste,in which case a physical combination of xylitol with the drug has thedual effect of providing xylitol to the patient and masking the badtaste of the drug. A combination of polyols may also be used.

Among the antifungal drugs used in the treatment of oral mucositis,drugs such as nystatin, amfotericin B, and various azoles may bementioned. In the therapy of oral candidiasis where xylitol alone is notconsidered sufficient, it is preferred to use nystatin in combinationwith the xylitol at least until the lesions are cured.

It is preferred to provide the xylitol to be used for the prevention orinhibition of mucositis in the form of an orally administrablepreparation. Such a preparation may be in the form of a liquid, atablet, a pill, a lozenge, a chewing gum or tablet, a powder, a spray, asyrup, a sugar substitute, a candy or sweet, an ice-cream, a pet food,an animal feed, and the like. The preparation may be produced by mixingat least one pharmacologically acceptable carrier and an amount ofxylitol sufficient to reduce or inhibit the infectious activity ofyeasts on the mucosa.

The amount of polyol included in any specific preparation of coursedepends on how much of the preparation in question that would be takenper day by the patient. The dose should be high enough to provide asignificant effect on the yeast infection but not too high to cause themammal adverse reactions in the form of diarrhea or flatulence. On theother hand, the effect of xylitol has been found to be dose dependent inthe sense that an increased level of xylitol causes a more markedreduction of yeast growth.

A suitable amount of xylitol in a preparation may be calculated so as togive the mammal a daily oral xylitol dose of about 0.05 to 1.0 g xylitolper kg of body weight, preferably 0.1 to 0.8 g/kg and most preferablyabout 0.2 to 0.5 g/kg. Higher amounts of xylitol may be given forshorter periods, but it should be noted that high doses of xylitol mayhave adverse effects on some patients, most notably in the form ofdiarrhea.

One easy way of providing for a suitable oral intake of polyol is toadminister the polyol as a sugar substitute in the diet of the patient.

In connection with oral mucosal infections the oral administration is atthe same time a topical administration. The polyol may also be appliedlocally to other infection areas. Such topically administrablepreparations may be in the form of a liquid, a spray, an aerosol, acream, a paste, a cement, an ointment, a jelly or gel, a lubricant, aplaster, a membrane, a mouth wash or rinse, a tooth paste, eye drops,etc. They may be prepared, for instance, by mixing at least one topicalcarrier and an amount of xylitol sufficient to reduce or inhibit theinfectious activity of yeasts on the mucosa.

For the specific use of xylitol in combating vaginal infection, thespecific topical composition should be in a form suitable for vaginaluse. The xylitol may thus be included in a cream, jelly, lubricant, orliquid or it may preferably be applied onto the surface of a condom.

In present times it has become popular to provide condoms with variousflavors, such as strawberry or banana. Correspondingly, the polyol suchas xylitol may be added to condoms as an antifungal humectant andsweetener compound. Thus, the condom embodiment of the inventionprovides an easy way of providing xylitol to infected or potentiallyinfectious mucosa at orifices of the human body, such as the vagina.

For the specific use of the polyol in combating udder infection in cows,the topical composition should preferably be in a form suitable forbeing easily applied on a farm. Xylitol is preferably included in aliquid spray or a dip. The xylitol may, however, also be included in amoist tissue.

For oral intake by pet animals, cattle, etc. the xylitol may be includedin a xylitol containing food or feed additive. The additive may containother polyols but it preferably should not contain glucose. The amountof xylitol in the additive should be more than 10% and it shouldpreferably be over 30%, most preferably over 40% of the total polyolcontent of the additive. The most preferred additive would be onewherein 50 to 100% of said polyol is xylitol. Such a product might,however, be too expensive for normal use and it is therefore suggestedto mix the xylitol with other components such as non-toxic,non-carbohydrate excipients.

The polyol may also be mixed directly into pet food or animal feedpreparations in an amount to provide a daily dose of about 0.05 to 1,0 gxylitol per kg of body weight, preferably 0.1 to 0.8 g/kg and mostpreferably about 0.2 to 0.5 g/kg.

The invention will now be illustrated further with the aid of a fewexamples. It should be noted that these examples are not to be construedas limiting the invention in any way.

EXAMPLE 1

A pilot study was designed to test the effect of xylitol on the clinicalcourse, Candida salivary counts, and antifungal needs of patients withrecurrent oral candidiasis. The patients were instructed to replacetheir dietary saccharose with crystalline xylitol and to avoid excesssaccharose-containing-foods and beverages.

Of 14 patients admitted to the test, 8 completed more than 14 days offollow up. The result was that all 8/8 experienced at least 70%regression of their lesions (improvement) with minimal antifungaltherapy (1 nystatin tablet 500,000 U/per day); 5/8 had completeregression of the lesions (cure); and 6/8 decreased their salivaryCandida counts by 2 logs.

Three patients returned to baseline 3 days after returning to saccharoseintake. 1 patient completed 4 months of xylitol intake without lesionsand sterile fungal cultures, having had a previously identifiedfluconazole resistant isolate (E test).

The results show that oral administration of xylitol instead of dietarysaccharose affected the pathogenesis of oral candidiasis and in somepatients improved the efficacy of antifungal therapies.

EXAMPLE 2

An open label, pilot trial was designed to test the effect of thestrategy of dietary xylitol intake in replacement of sugar in patientswith candida mucositis. AIDS patients with oral or esophagealcandidiasis were selected as subjects for the study because of thefrequency and the severity of candida mucositis that they usuallydevelop.

Patients with AIDS were considered eligible for the test after theiroral or esophageal lesions were documented by microscopic examination ofscrapings to be of Candida origin. They were free to continue on anyantifungal therapy they might be receiving.

Instructions were given to replace the saccharose that they normallytake with coffee or tea for crystalline xylitol. Also, to avoid excesssweets like ice cream, cakes. cookies, and artificially flavored drinksthat contain glucose.

The following was done at baseline and thereafter every 7 days:

1. Pictures of the lesions

2. Tongue imprints in Sabouraud agar

3. Quantitative Candida cultures on unstimulated saliva (CFU/ml)

4. Pain questionnaire (numerical pain scale)

5. Weight

6. Patients kept a daily record of food and drink.

AIDS patient No. 1 had suffered from oral candidiasis for about 9 monthswith episodes of oral candidiasis recurring with almost no symptom-freeperiods. The patient received AZT as antiretroviral therapy andketoconazole as antifungal therapy.

The patient noticed clear improvement on day four of the trial andvoluntarily discontinued ketoconazole at this point. The lesionscontinued to improve and disappeared after 1 week in the trial. TheCandida counts that were 1×10⁴ on day one, became negative at day seven,and were still negative after 2.5 months.

The patient completed a symptom-free, follow-up period of 80 days, andgained 13.1 kilograms weight (From 62 to 75.1 kg) The daily xylitolintake was approximately 6-8 sugar spoons (about 30 g) of crystallinexylitol. The results are shown below in Table 1.

TABLE 1 Day 1 8 18 29 36 56 80 CFU/mL 1 × 10⁴* 0** 0** 0** 0** 0** 0**saliva Sympt. 18 0  0   0 0   0 0  score Weight 62 62.6 73.4 73 74.8 7575.1 (Kg) *counted at 48 hours **plates held for 7 days before callingthem sterile

AIDS patient No 2 was diagnosed to have Candida esophagitis but wasreceiving no antifungal therapy. Two weeks after the start of xylitolintake the patient had unchanged lesions and was started on fluconazolep.o. for a 15 days period. Follow up esophagoscopy done a month laterrevealed no lesions. The results are shown below in Table 2.

TABLE 2 Day 1 7 15 22 29 36 50 CFU/ml 6 × 0 3,6 × 10³** 4,5 × 10²** 0 00 saliva 10²* Sympt. 18 0 0 0 0 0 0 score Weight 58,5 58,5 58,5 57,557,2 57,7 56,9 (Kg) *counted at 48 hours **counted at 72 hours (unableto count at 48 hours, as colonies were too small)

AIDS patient No. 3 had recurrent oral candidiasis for nearly two yearswith multiple recurrences and almost no symptom-free periods. There wasno longer any response to antifungal multiple therapies with azoles. Theoral mucosa was totally covered with white plaques. There wasconsiderable pain.

The patient kept taking 1 nystatin troche during the first five days ofthe xylitol trial. The pain symptoms were reduced from 30 to 8 in thefirst 17 days and the saliva counts diminished. However, the patientthen got another illness and retired from the trial.

The oral candidiasis recurred 4 days after stopping the xylitol trial.

EXAMPLE 3

Candida isolate from AIDS patient No 1of Example 2 was tested forsensitivity and was found to be resistant to Fluconazole (MIC>256 μg/ml)and sensitive to Amphotericin B.

The effect of sugar alcohols on the growth of said Candida isolate wastested on Muller Hinton agar with 5 and 10% glucose or 5 and 10% xylitoland a control without sugar. The growth was found to be inhibited in adose dependent way by xylitol when compared to the controls (FIG. 1).Glucose increased the growth quite considerably.

EXAMPLE 4

A test was designed to determine the effect on the growth in vitro ofCandida albicans of xylitol, lactitol, sorbitol and aspartame incomparison to glucose and a non-carbohydrate control medium. The testedsubstances have all been used in the food industry as sweeteners. Thesweetness of the substances in the above order is respectively 100%,40%, 60% and 20.000% of the sweetness of glucose.

12 strains of Candida albicans obtained from patients with AIDS and oralcandida mucositis were evaluated. The strains were inoculated onSabouraud agar plates (20% dextrose) and incubated at room temperaturefor 48 hours. One colony from each plate was inoculated in Muller Hintonbroth (without sweetener) and left for 18 hours at 35° C. The tubes werestandardized to Mac Farland 0.5 (5×10⁶ CFU/ml) and 100 μl inoculated intriplicate in spectrophotometer tubes containing 3 ml of Muller Hintonbroth at final concentrations of glucose (5% and 10%); xylitol (5% and10%); lactitol (5%, 8.3% and 10%); sorbitol (5%, 10% and 12.5%); andaspartame (0.025% and 0.05%). 3 tubes with Muller Hinton broth withoutcarbohydrate was also inoculated to serve as controls.

Optical densities (650 nm) were determined at 0, 24 and 48 hours time.The average of three readings per time, per sweetener concentration wascalculated and recorded. The results of the test are indicated in FIG. 2showing the summary curve of the averages of all the strains in each ofthe test mediums.

The results clearly indicate that glucose has an effect of increasingthe growth of Candida in comparison to the control without carbohydrate.The artificial sweeteners all reduced the growth of Candida compared tothe control. Xylitol at 10% concentration proved to be by far the bestof the tested compounds at reducing the growth of Candida in vitro.

What is claimed is:
 1. A method for the therapeutic or prophylactictreatment of mammals suffering from or being subject to an increasedrisk of mucosal yeast infection, said method comprising administering tosaid mammal, a polyol in an amount which is effective in reducing orinhibiting mucosal infection caused by yeast in said mammal, oreffective in enhancing the effect of other antifungal drugs used in thetreatment of said infection.
 2. The method according to claim 1 whereinthe polyol is the sole active agent in the treatment or prophylaxis ofmucosal infection.
 3. The method according to claims 1 or 2 wherein thepolyol is selected from the group consisting of xylitol, lactitol,sorbitol, mannitol and mixtures thereof.
 4. The method according toclaims 1 or 2 wherein said yeast is a Candida s.p.
 5. The methodaccording to claims 1 or 2 wherein said mucosal infection is aninfection of the mucosa in connection with exocrine glands of the bodyof said mammal.
 6. The method according to claims 1 or 2 wherein saidmammal is selected from the group consisting of human beings, mammalianpet animals, and mammalian farm animals.
 7. The method according toclaim 6, wherein said mammal is a human being suffering from AIDS. 8.The method according to claims 1 or 2 wherein said polyol isadministered by systemic or topical administration.
 9. The methodaccording to claim 8, wherein xylitol is administered orally.
 10. Themethod according to claims 1 or 2 wherein xylitol is administered as asugar substitute in the diet of said mammal.
 11. The method according toclaim 10, wherein said mucosal yeast infection is an oral infection,especially oral candidiasis.
 12. The method according to claims 1 or 2wherein said mucosal yeast infection is a vaginal infection.
 13. Themethod according to claims 1 or 2 wherein said mucosal yeast infectionis mastitis or an udder infection.
 14. A composition for use in thetherapeutic or prophylactic treatment of mammals suffering from or beingsubject to an increased risk of mucosal yeast infections, containing atleast one pharmacologically acceptable carrier and an amount of polyolsufficient to reduce or inhibit mucosal infection caused by yeast insaid mammal.
 15. The composition according to claim 14 wherein thepolyol is the sole active agent in the treatment or prophylaxis ofmucosal infection and the polyol is selected from the group consistingof xylitol, lactitol, sorbitol, mannitol and mixtures thereof.
 16. Themethod according to claim 6, wherein said Candida s.p. is Candidaalbicans.
 17. The composition according to claim 14, wherein said yeastis Candida s.p.
 18. The composition according to claim 17, wherein saidCandida s.p. is Candida albicans.
 19. The method according to claim 3,wherein said polyol is xylitol.
 20. The composition according to claim3, wherein said polyol is xylitol.